US4673567A - Process for preparing liposome composition - Google Patents

Process for preparing liposome composition Download PDF

Info

Publication number
US4673567A
US4673567A US06/763,785 US76378585A US4673567A US 4673567 A US4673567 A US 4673567A US 76378585 A US76378585 A US 76378585A US 4673567 A US4673567 A US 4673567A
Authority
US
United States
Prior art keywords
vesicles
freeze
dried
liposome
aqueous medium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/763,785
Inventor
Hiroaki Jizomoto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Assigned to SHIONOGI & CO., LTD., FUKUSHIMA-KU, OSAKA, JAPAN reassignment SHIONOGI & CO., LTD., FUKUSHIMA-KU, OSAKA, JAPAN ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: JIZOMOTO, HIROAKI
Application granted granted Critical
Publication of US4673567A publication Critical patent/US4673567A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1277Processes for preparing; Proliposomes

Definitions

  • the present invention relates to processes for preparing liposome compositions.
  • a process to prepare liposome compositions is disclosed in JPN Unexam. Pat. Pub. No. 53-142514 where the liposome compositions which have been formulated and phospholipid, an active ingredient, and adjuvants are lyophilized for stable storage. According to other processes disclosed in JPN Unexam. Pat. Pub. Nos. 57-82310 and 57-82311, freeze-dried liposomes are prepared with no organic solvent and are formulated into liposome compositions by the use of an aqueous medium which may or may not contain an active ingredient.
  • This invention provides processes for preparing liposome compositions which comprises dispersing multilamella vesicles or small unilamella vesicles in an aqueous medium in the presence of one or more clinically active ingredients at or over a temperature of the gel-phase/liquid crystal-phase transition wherein lyophilization may be made before or after the dispersion.
  • the regenerated liposomes are generally in the form of multilamella vesicles (hereinafter referred to as MLV).
  • MLV multilamella vesicles
  • the present inventor has studied with the purpose of obtaining regenerated liposomes, each of which has a large captured volume and is capable to highly entrap an active ingredient in the room, when preparing liposome compositions by dispersing freeze-dried liposomes in an aqueous medium.
  • liposome compositions by dispersing freeze-dried liposomes in an aqueous medium, it should be confirmed that liposomes can, even if the lipid of them is composed of a lecithin, be regenerated when the system is operated at an elevated temperature over the gel-/liquid crystal-phase transition temperature with regard to the lecithin involved.
  • Active ingredients to be entrapped may be ⁇ 1 added by way of lyophilization of the liposomes, or ⁇ 2 added to the freeze-dried liposomes; the resulting mixtures being employed for the completion of this invention. Additionally, the process of the present invention can be employed in the course of dispersing freeze-dried liposomes in an aqueous medium where active ingredients are dissolved or dispersed.
  • Lecithins i.e., saturated or unsaturated phosphatidyl choline, which are lipids composing liposome, are employed for this invention. These lecithins may contain phosphatidyl serine, phosphatidyl ethanolamine, phosphatidyl inositol, diphosphatidyl glycolol, phosphatidate, sphingomyelin, or the like; and further contain cholesterol or electrically charged substances (e.g., stearylamine, dicetylphosphate).
  • lecithins may be derived from yolk, soybean, or tissues of the other animals or plants, hydrogenates thereof, and synthetic lecithins, which lecithins may be employed individually or in admixture of them.
  • dipalmitoyl ⁇ phosphatidylcholine, distearoyl ⁇ phosphatidylcholine, 1-palmitoyl-2-strearoyl ⁇ phosphatidylcholine, 1-stearoyl-2-palmitoyl ⁇ phosphatidylcholine, and the like can be employed solely or in combination.
  • the gel-/liquid crystal-phase transition temperature of the usual lipids is listed in a disclosure of Ann. Rev. Bioeng., 9, 467 (1980).
  • a heating operation is not, of course, required in the regeneration step of the gel-/liquid crystal-phase transition temperature is room temperature or below; this case, therefore, does not fall within the scope of this invention.
  • the freeze-dried liposomes employed in this invention are the freeze-dried MLV or SLV prepared by the known method, which may be obtained by means of any method for lyophilization.
  • the active ingredients involved are anti-cancer agents such as 5-fluorouracil, neomycin, bleomycin, or the like; antibiotic agents such as cefalexin, latamoxef, or the like; enzymes or homologues such as urokinase or the like; peptides such as interferon, interleukin, globulin, insulin or the like; nucleic acids such as DNA, RNA, or the like; vitamins; or the other agents such as sulfamethoxazole, phenobarbital, or the like.
  • the thus-obtained liposome compositions may be orally or parenterally administered to subjects directly or in the state of a purified dispersion by removing the excessive active agent remaining outside the liposome by means of centrifugal separation, ultrafiltration, gelfiltration, or the like.
  • the liposome compositions prepared by the present invention the uptake-rate into which is high, envelop the aimed active ingredient therein with high efficiency. Since each regenerated liposome has a large captured volume, a large amount of the active ingredient can be entrapped in it by a less amount of the lipid. This means that the liposome compositions can present problems, such as toxicity due to phospholipid when they are administered, or the like.
  • both liposome and active ingredients can be stored in a stable state, because the active ingredient to be entrapped may be admixed at the time when the freeze-dried liposomes are regenerated.
  • the uptake rate was calculated by the following formula: ##EQU1##
  • the active ingredient taken into the liposome is released with Triton® ⁇ -100 and quantitatively analyzed by liquid chromatography.
  • the captured volume was calculated by the following formula:
  • Ultra-sonic wave (Daigaku ultra-sonic wave grinder, medium size tip, 120W ⁇ 3 minutes) was radiated onto the MLV dispersion prepared with 300 mg of DPPC (Sigma I) in the same manner as in Example 1 to give a suspension of SUV.
  • the SUV suspension was subject to cetrifugal separation (85,000 g ⁇ 30 minutes), and then the supernatant was freeze-dried like in Example 1.
  • freeze-dried sample of SUV was employed for such regeneration test as in Example 1.
  • the results are summarized in Table 2.
  • Referrence ⁇ 5 shows the comparative test result which was obtained by merely mixing the freeze-dried liposomes with an aqueous solution of 5-FU at room temperature, without heating over the phase transition temperature concerning the membrance.
  • Example 2 To a mixture of 10 mg of freeze-dried sample of MLV obtained in Example 1 with 2 mg of crystalline 5-FU was added 0.4 ml of purified water. The suspension was swelled and dispersed well and kept at 50° C. for 5 minutes. In the same manner as in Example 1, the uptake rate into liposome was measured thereafter: the uptake rate and captured volume were 37.5% and 14.5 ⁇ l/mg, respectively.
  • Example 2 To 30 mg of the freeze-dried sample of MLV obtained in Example 1 was added 0.2 ml of an insulin solution (at 10 mg/ml, containing 0.01N hydrogen chloride). The mixture was ⁇ 1 warmed up and kept at 50° C. for 10 minutes, ⁇ 2 allowed to stand at room temperature. Or ⁇ 3 after 30 mg of the sample was warmed up and kept at 50° C. for 10 minutes, insulin was added thereto. In the same manner as in Example 1, the uptake rates of insulin thereinto were measured and the data are summarized in Table 4.
  • the liposome-water suspension prepared from L-DPPC (Avanti Polar Lipids, Inc., 100 mg) and stearylamine (0.37 mg) by a similar method to Example 7 was freeze-dried.

Abstract

Novel process for liposome compositions capable to retain larger amount of drugs with a small amount of phospholipid and to provide, therefore, safer medications of various drugs, which comprises dispersing multilamella vesicles or small unilamella vesicles in an aqueous medium in the presence of one or more clinically active ingredients at or over a temperature of the gel/liquid crystal-phase transition wherein lyophilization may be made before or after the dispersion.

Description

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to processes for preparing liposome compositions.
2. Prior Art
A process to prepare liposome compositions is disclosed in JPN Unexam. Pat. Pub. No. 53-142514 where the liposome compositions which have been formulated and phospholipid, an active ingredient, and adjuvants are lyophilized for stable storage. According to other processes disclosed in JPN Unexam. Pat. Pub. Nos. 57-82310 and 57-82311, freeze-dried liposomes are prepared with no organic solvent and are formulated into liposome compositions by the use of an aqueous medium which may or may not contain an active ingredient.
On the other hand, a process is disclosed in the JPN Unexam. Pat. Pub. No. 58-152812, wherein small unilamella vesicles (hereinafter referred to as SUV) or large unilamella vesicles (hereinafter referred to as LUV) are prepared by dispersing a special phospholipid in an aqueous medium having a specific pH-value.
SUMMARY OF THE INVENTION
This invention provides processes for preparing liposome compositions which comprises dispersing multilamella vesicles or small unilamella vesicles in an aqueous medium in the presence of one or more clinically active ingredients at or over a temperature of the gel-phase/liquid crystal-phase transition wherein lyophilization may be made before or after the dispersion.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Problem
In the prior art, when freeze-dried liposome compositions are dispersed in an aqueous medium, which may or may not contain an active ingredient, the regenerated liposomes are generally in the form of multilamella vesicles (hereinafter referred to as MLV). This means that each room of regenerated liposomes (captured volume) is small and, therefore, the uptake rate of the active ingredient into the room is low. Additionally, if a freeze-dried liposome prepared from synthetic lecithin is dispersed in an aqueous medium at room temperature, even liposome is not regenerated.
The present inventor has studied with the purpose of obtaining regenerated liposomes, each of which has a large captured volume and is capable to highly entrap an active ingredient in the room, when preparing liposome compositions by dispersing freeze-dried liposomes in an aqueous medium.
Means for Resolving the Problem
In order to prepare liposome compositions by dispersing freeze-dried liposomes in an aqueous medium, it should be confirmed that liposomes can, even if the lipid of them is composed of a lecithin, be regenerated when the system is operated at an elevated temperature over the gel-/liquid crystal-phase transition temperature with regard to the lecithin involved.
Active ingredients to be entrapped may be ○1 added by way of lyophilization of the liposomes, or ○2 added to the freeze-dried liposomes; the resulting mixtures being employed for the completion of this invention. Additionally, the process of the present invention can be employed in the course of dispersing freeze-dried liposomes in an aqueous medium where active ingredients are dissolved or dispersed.
Lecithins, i.e., saturated or unsaturated phosphatidyl choline, which are lipids composing liposome, are employed for this invention. These lecithins may contain phosphatidyl serine, phosphatidyl ethanolamine, phosphatidyl inositol, diphosphatidyl glycolol, phosphatidate, sphingomyelin, or the like; and further contain cholesterol or electrically charged substances (e.g., stearylamine, dicetylphosphate). Such lecithins may be derived from yolk, soybean, or tissues of the other animals or plants, hydrogenates thereof, and synthetic lecithins, which lecithins may be employed individually or in admixture of them. For instance, dipalmitoyl═phosphatidylcholine, distearoyl═phosphatidylcholine, 1-palmitoyl-2-strearoyl═phosphatidylcholine, 1-stearoyl-2-palmitoyl═phosphatidylcholine, and the like can be employed solely or in combination.
The gel-/liquid crystal-phase transition temperature of the usual lipids is listed in a disclosure of Ann. Rev. Bioeng., 9, 467 (1980). A heating operation is not, of course, required in the regeneration step of the gel-/liquid crystal-phase transition temperature is room temperature or below; this case, therefore, does not fall within the scope of this invention.
The freeze-dried liposomes employed in this invention are the freeze-dried MLV or SLV prepared by the known method, which may be obtained by means of any method for lyophilization. Examples of the active ingredients involved are anti-cancer agents such as 5-fluorouracil, neomycin, bleomycin, or the like; antibiotic agents such as cefalexin, latamoxef, or the like; enzymes or homologues such as urokinase or the like; peptides such as interferon, interleukin, globulin, insulin or the like; nucleic acids such as DNA, RNA, or the like; vitamins; or the other agents such as sulfamethoxazole, phenobarbital, or the like.
Water, brine (e.g., isotonic brine), buffer (e.g., phosphate buffer, trisaminomethane buffer) or the like is employed as an aqueous medium in which the freeze-dried liposome are dispersed; the choice depending on the purposes for which the resulting liposome composition is used. The thus-obtained liposome compositions may be orally or parenterally administered to subjects directly or in the state of a purified dispersion by removing the excessive active agent remaining outside the liposome by means of centrifugal separation, ultrafiltration, gelfiltration, or the like.
Effects
The liposome compositions prepared by the present invention, the uptake-rate into which is high, envelop the aimed active ingredient therein with high efficiency. Since each regenerated liposome has a large captured volume, a large amount of the active ingredient can be entrapped in it by a less amount of the lipid. This means that the liposome compositions can present problems, such as toxicity due to phospholipid when they are administered, or the like.
Additionally, both liposome and active ingredients can be stored in a stable state, because the active ingredient to be entrapped may be admixed at the time when the freeze-dried liposomes are regenerated.
The present invention will be explained in more detail by the following examples, which are not presented to limit the scope of this invention, but only to specifically describe the practical embodiments.
EXAMPLE 1
In chloroform was dissolved 700 mg of D,L-dipalmitoylphosphatidyl choline (DPPC) (type grade I, Sigma Chemical Co., Ltd.), then the chloroform was removed by a rotary-evaporator to form a thin layer of phospholipid on the inner wall of the round-bottom flask. The phospholipid was dried sufficiently under reduced pressure, to which 25 ml of water was added. The mixture was shaken by hand at 50° C. for about 7 minutes to give an dispersion of MLV. The dispersion was frozen by the use of dry ice/acetone and dried by vacuum lyophilization. The powder obtained was collected, 10 mg of which was then weighed and placed in each tube for centrifugal separation. A solution of 5-Fluorouracil (5-FU) (5 mg/ml) dissolved in purified water, 2- and 10-fold diluted aqueous isotonic sodium chloride solutions, and 0.02M phosphate buffer was added into the tubes in amounts of 0.4 ml each. The mixture was swelled and dispersed well, then warmed up and kept at 50° C. for five minutes and washed twice with an isotonic phosphate buffer solution (pH 7.4) at room temperature by means of ultra-centrifugal separation (85, 000 g×60 minutes). The uptake rate of 5-FU into liposome and the captured volume of liposome are listed in Table 1.
The uptake rate was calculated by the following formula: ##EQU1##
The active ingredient taken into the liposome is released with Triton®×-100 and quantitatively analyzed by liquid chromatography.
In the case of 5-FU, the conditions of the chromatography are:
Nucleocil 10 C18, 0.05M potassium dihydrogenphosphate/acetatonitrile=75/25, 265 nm.
The captured volume was calculated by the following formula:
[(Volume (μl) of aqueous solution of the active ingredient employed)×(Uptake rate)]/(Weight (mg) of lipid employed)
Before this experiment, it was confirmed that 5-FU was never adsorbed on the liposome layer.
              TABLE 1                                                     
______________________________________                                    
Freeze-dried sample of DPPC-MLV with 5-FU                                 
            Ionic Strength                                                
                        Uptake rate                                       
                                  Captured Vol                            
Solvent     (I)         (%)       (μl/mg)                              
______________________________________                                    
Purified water                                                            
            0           41.8      16.6                                    
1/10 Isotonic brine                                                       
            0.015       29.7      11.6                                    
1/2 Isotonic brine                                                        
            0.077       3.8       1.5                                     
0.02 M phosphate                                                          
            0.052       5.2       1.9                                     
buffer                                                                    
______________________________________                                    
EXAMPLE 2
Ultra-sonic wave (Daigaku ultra-sonic wave grinder, medium size tip, 120W×3 minutes) was radiated onto the MLV dispersion prepared with 300 mg of DPPC (Sigma I) in the same manner as in Example 1 to give a suspension of SUV. The SUV suspension was subject to cetrifugal separation (85,000 g×30 minutes), and then the supernatant was freeze-dried like in Example 1. Thus obtained freeze-dried sample of SUV was employed for such regeneration test as in Example 1. The results are summarized in Table 2. Referrence ○5 shows the comparative test result which was obtained by merely mixing the freeze-dried liposomes with an aqueous solution of 5-FU at room temperature, without heating over the phase transition temperature concerning the membrance.
              TABLE 2                                                     
______________________________________                                    
Freeze-dried sample of DPPC-SUV with 5-FU                                 
                  Uptake rate                                             
                             Captured Vol.                                
Solvent           (%)        (μl/mg)                                   
______________________________________                                    
 ○1                                                                
     Purified water   36.7       14.3                                     
 ○2                                                                
     1/10 Isotonic brine                                                  
                      22.4       8.6                                      
 ○3                                                                
     1/2 Isotonic brine                                                   
                      1.3        0.5                                      
 ○4                                                                
     0.02 M Phosphate buffer                                              
                      1.9        0.7                                      
 ○5                                                                
     Purified water (at r.t.)                                             
                      0.1        0.04                                     
______________________________________                                    
EXAMPLE 3
To a mixture of 10 mg of freeze-dried sample of MLV obtained in Example 1 with 2 mg of crystalline 5-FU was added 0.4 ml of purified water. The suspension was swelled and dispersed well and kept at 50° C. for 5 minutes. In the same manner as in Example 1, the uptake rate into liposome was measured thereafter: the uptake rate and captured volume were 37.5% and 14.5 μl/mg, respectively.
EXAMPLE 4
Cefalexin (5 mg/ml) or latamoxef (3 mg/ml) in place of 5-FU in Example 1 was employed for the test together with a solvent of purified water, 1/2 isotonic brine, or 0.05M phosphate buffer solution (pH 7.4). The results are listed in Table 3. Data on liposome (MLV) enveloping latamoxef are also shown as a referrence, which were obtained by the conventional hydration method (a method that an aqueous solution containing an active ingredient was employed in place of purified water when MLV was prepared as explained in Example 1). The relative ratio of the volume of aqueous solution containing an active ingredient to a unit weight of the lipid was kept in a prefixed condition (40 μl/mg lipid) throughout the tests. The mixture was warmed up at 50° C. for 2 minutes. The ingredients are quantitatively analyzed by a liquid chromtography where the condition is: Nucleocil 10 C18, 0.02M phosphate buffer (pH 7.4)/methanol=60/35, at 270 nm in case of cefalexin; 0.05 M ammonium acetate/methanol=11/1, at 276 nm in case of latamoxef.
              TABLE 3                                                     
______________________________________                                    
                  Uptake rate                                             
                            Captured Vol.                                 
Solvent           (%)       (μl/mg)                                    
______________________________________                                    
Freeze-dried sample of DPPC-MLV with cefalexin                            
 ○1                                                                
     Purified water   37.0      14.4                                      
 ○2                                                                
     1/2 Isotonic brine                                                   
                      3.4       1.3                                       
Freeze-dried sample of DPPC-MLV with latamoxef                            
 ○3                                                                
     Purified water   34.4      13.8                                      
 ○4                                                                
     0.05 M Phosphate buffer                                              
                      3.2       1.4                                       
 ○5                                                                
     Purified water (Hydra-                                               
                      10.1      4.0                                       
     tion method, MLV)                                                    
______________________________________                                    
EXAMPLE 5
Two freeze-dried samples of MLV containing stearylamine (SA) or dicetyl phosphate (DCP), and DPPC were prepared at a mole ratio of 1/9 (DPPC/SA) or 1/9 (DPPC/DCP). To 15 mg each of the respective samples was added 0.2 ml of an aqueous solution (10 mg/ml) of latamoxef, and the mixtures were warmed up and kept at 50° C. for one minute to give liposomes. The respective uptake rates of thus obtained liposomes are 42.3% and 28.7%.
EXAMPLE 6
To 30 mg of the freeze-dried sample of MLV obtained in Example 1 was added 0.2 ml of an insulin solution (at 10 mg/ml, containing 0.01N hydrogen chloride). The mixture was ○1 warmed up and kept at 50° C. for 10 minutes, ○2 allowed to stand at room temperature. Or ○3 after 30 mg of the sample was warmed up and kept at 50° C. for 10 minutes, insulin was added thereto. In the same manner as in Example 1, the uptake rates of insulin thereinto were measured and the data are summarized in Table 4.
              TABLE 4                                                     
______________________________________                                    
Freeze-dried sample of DPPC-MLV with insulin                              
                           Uptake                                         
Procedures employed        rate %                                         
______________________________________                                    
 ○1                                                                
      Warming up after addition of insulin                                
                               60.5                                       
 ○2                                                                
      Allowed to stand at room temperature after                          
                               3.0                                        
      addition of insulin                                                 
 ○3                                                                
      Adding insulin after the warming up                                 
                               1.6                                        
______________________________________                                    
EXAMPLE 7
A mixture of DL-DPPC (Sigma Chemical Co., type I-S, 200 mg) and dicetyl phosphate (1.5 mg) dissolved in chloroform was added to a 200 ml round-bottom flask and the solvent removed under reduced pressure by a rotary evaporator. To the thin dry lipid-film, 10 ml of distilled water was added, and gentle shaking was carried out at 50° C. The suspension was then freezed in a bath of dry ice-acetone and freeze-dried by a rotary vaccum pump.
To 10 mg of the freeze-dried product was added 0.4 ml of 5FU (2.5 mg/ml) aqueous solution which contained 10 μmol/ml CaCl2 was added. After standing for 1 hour at room temperature, this system was warmed up for 5 minutes at 50° C. and 5FU-entrapped liposomes were prepared. The percentage of 5FU captured in liposomes was measured by a similar method to Example 1.
The results indicated that the percentage was 33% and the captured volume was 13.3 μl/mg lipid.
EXAMPLE 8
The liposome-water suspension prepared from L-DPPC (Avanti Polar Lipids, Inc., 100 mg) and stearylamine (0.37 mg) by a similar method to Example 7 was freeze-dried. To 10 mg of the freeze-dried product, 0.4 ml of 5FU (2.5 mg/ml) aqueous solution was added. After standing for 1 hour at room temperature, the system was warmed up for 5 minutes at 50° C. and 5FU-entrapped liposomes were prepared. The percentage of 5FU captured in liposomes was measured by a similar method to Example 1.
The results indicated that the percentage was 44% and the captured volume was 19 μl/mg lipid.

Claims (4)

What is claimed is:
1. A process for preparing liposome compositions which comprises dispersing lyophilized multilamella vesicles or small unilamella vesicles in an aqueous medium in the presence of one or more clinically active ingredients at or over a temperature of the gel-phase/liquid crystal-phase transition.
2. A process claimed in claim 1, wherein said active ingredients are admixed with the vesicles before the lyophilization of said multilamella vesicles or small unilamella vesicles.
3. A process claimed in claim 1, wherein said active ingredients are admixed with said lyophilized multilamella vesicles or small unilamella vesicles and then dispersed in the aqueous medium.
4. A process claimed in claim 1, wherein the active ingredient is added in advance to the aqueous medium.
US06/763,785 1984-08-16 1985-08-08 Process for preparing liposome composition Expired - Lifetime US4673567A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP59171265A JPS6150912A (en) 1984-08-16 1984-08-16 Production of liposome preparation
JP59-171265 1984-08-16

Publications (1)

Publication Number Publication Date
US4673567A true US4673567A (en) 1987-06-16

Family

ID=15920119

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/763,785 Expired - Lifetime US4673567A (en) 1984-08-16 1985-08-08 Process for preparing liposome composition

Country Status (4)

Country Link
US (1) US4673567A (en)
EP (1) EP0171710A3 (en)
JP (1) JPS6150912A (en)
GB (2) GB8520405D0 (en)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4765987A (en) * 1985-08-30 1988-08-23 Adir & Cie Artificial surfactants, pharmaceutical compositions containing them and use thereof
WO1989005636A1 (en) * 1987-12-22 1989-06-29 The Liposome Company, Inc. Spontaneous vesiculation of multilamellar liposomes
US4877561A (en) * 1986-04-02 1989-10-31 Takeda Chemical Industries, Ltd. Method of producing liposome
WO1989011272A1 (en) * 1988-05-20 1989-11-30 The Liposome Company, Inc. High ratio active agent:lipid complex
US4963362A (en) * 1987-08-07 1990-10-16 Regents Of The University Of Minnesota Freeze-dried liposome mixture containing cyclosporin
US4963297A (en) * 1987-12-22 1990-10-16 The Liposome Company, Inc. Spontaneous vesticulation of multilamellar liposomes
US4971802A (en) * 1984-10-16 1990-11-20 Ciba-Geigy Corporation Liposomes of synthetic lipids
US4999348A (en) * 1987-12-11 1991-03-12 Estee Lauder Inc. Liquid crystal containing cosmetic and pharmaceutical compositions and methods for utilizing such compositions
US5015483A (en) * 1989-02-09 1991-05-14 Nabisco Brands, Inc. Liposome composition for the stabilization of oxidizable substances
WO1992012703A1 (en) * 1991-01-15 1992-08-06 University Of Miami Stimulation of hair growth by phospholipids
US5139803A (en) * 1989-02-09 1992-08-18 Nabisco, Inc. Method and liposome composition for the stabilization of oxidizable substances
US5178875A (en) * 1991-01-14 1993-01-12 The Board Of Regents, The University Of Texas System Liposomal-polyene preliposomal powder and method for its preparation
US5246693A (en) * 1989-12-13 1993-09-21 L'oreal Cosmetic preparation for the care of the hair and use of the said composition
US5376380A (en) * 1990-08-21 1994-12-27 Daiichi Pharmaceutical Co., Ltd. Method of producing liposomal products from freeze or spray-dried preparations of liposomes
US5393530A (en) * 1990-12-11 1995-02-28 Bracco International B.V. Method for making liposomes of enhanced entrapping capacity toward foreign substances to be encapsulated
US5415867A (en) * 1988-04-20 1995-05-16 The Liposome Company, Inc. High ratio active agent: lipid complex
US5620703A (en) * 1991-10-11 1997-04-15 Max-Delbruck-Centrum Fur Molekulare Medizin Stimulating hematopoietic activity with carboplatin or lobaplatin
US5830499A (en) * 1994-09-27 1998-11-03 Rijksuniversiteit Leiden Phospholipid-and cholestrol-free aqueous composition for topical application to the skin
US5830498A (en) * 1987-10-16 1998-11-03 Board Of Regents, The University Of Texas System Liposomal-polyene preliposomal powder and method for its preparation
US20020143177A1 (en) * 2000-06-30 2002-10-03 Beck James P. Compounds to treat alzheimer's disease
US20020150566A1 (en) * 2001-03-23 2002-10-17 Kun-Liang Guan Method of inhibiting cancerous cell proliferation using Ras mutants of GDP-bound conformation
WO2003000202A2 (en) * 2001-06-22 2003-01-03 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
US20030083518A1 (en) * 2001-06-27 2003-05-01 Varghese John Substituted alcohols useful in treatment of Alzheimer's disease
US6727079B1 (en) 1998-02-25 2004-04-27 The United States Of America As Represented By The Department Of Health And Human Services cDNA encoding a gene BOG (B5T Over-expressed Gene) and its protein product
US6737420B2 (en) 2000-03-23 2004-05-18 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US6992081B2 (en) 2000-03-23 2006-01-31 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US7034182B2 (en) 2000-06-30 2006-04-25 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
WO2006057500A1 (en) 2004-11-24 2006-06-01 Seoul National University Industry Foundation Use of aimp2dx2 for the diagnosis and treatment of cancer
US20060140847A1 (en) * 2003-02-18 2006-06-29 Bo Yang Method for introducing functional material into organic nanotube
US7214715B2 (en) 2000-06-30 2007-05-08 Pharmacia & Upjohn Compounds to treat Alzheimer's disease
US20080171795A1 (en) * 2005-03-21 2008-07-17 Life-Care Innovations Pvt. Ltd. Novel Inter and Intra Multilamellar Vesicular Composition
US20090074746A1 (en) * 2000-06-30 2009-03-19 Alzheimer's Collaboration Compounds to treat alzheimer's disease
US20100260830A1 (en) * 2009-04-08 2010-10-14 Brian A Salvatore Liposomal Formulations of Tocopheryl Amides
WO2016100716A1 (en) 2014-12-18 2016-06-23 Vasant Jadhav Reversirtm compounds
US9944713B2 (en) 2004-11-24 2018-04-17 Medicinal Bioconvergence Research Center Antibody specific to the AIMP2-DX2
US10195166B2 (en) 2013-10-29 2019-02-05 The Catholic University Of Korea Industry-Academic Cooperation Foundation Methods for treating hepatitis C virus infectious disease

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2579625B2 (en) * 1985-07-05 1997-02-05 ザ リポソ−ム カンパニ−,インコ−ポレイテツド Multilamellar liposomes with improved uptake efficiency
JPS6328391A (en) * 1986-07-19 1988-02-06 Kanegafuchi Chem Ind Co Ltd Stabilized enzymic agent
JPS63211222A (en) * 1987-02-27 1988-09-02 Terumo Corp Production of liposome
EP0330124A3 (en) * 1988-02-24 1991-06-12 Toray Industries, Inc. Electroconductive integrated substrate and process for producing the same
KR940000166B1 (en) * 1989-11-09 1994-01-08 니혼다바고 상교오 가부시기가이샤 Novel glucosamine derivative and liposome containing the same as membrane component
JP2510044B2 (en) * 1989-12-28 1996-06-26 東芝セラミックス株式会社 Ceramic porous body
KR940004071B1 (en) * 1990-04-12 1994-05-11 니홍 다바꼬 상교 가부시끼가이샤 4,6-o-hydroxy phosphorylglucosamine derivatives
RU2093494C1 (en) * 1992-12-22 1997-10-20 Государственный научно-исследовательский институт конструкционных материалов на основе графита Method of manufacturing constructional heat-insulation carbon material and constructional heat-insulation carbon material
GB9320668D0 (en) 1993-10-07 1993-11-24 Secr Defence Liposomes containing particulare materials

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4217344A (en) * 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4235871A (en) * 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4298594A (en) * 1978-04-14 1981-11-03 Arthur D. Little, Inc. Xenobiotic delivery vehicles, method of forming them and method of using them
US4389330A (en) * 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
US4483847A (en) * 1980-06-28 1984-11-20 Warner-Lambert Company Process for the manufacture of a pharmaceutical composition with a retarded liberation of active material
US4485054A (en) * 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4515736A (en) * 1983-05-12 1985-05-07 The Regents Of The University Of California Method for encapsulating materials into liposomes
US4532089A (en) * 1984-01-14 1985-07-30 Northwestern University Method of preparing giant size liposomes
US4540410A (en) * 1982-11-16 1985-09-10 Serono Pharmaceutical Partners Lyophilized compositions, preparation and use thereof

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL246985A (en) * 1958-12-31
US3516943A (en) * 1966-12-06 1970-06-23 Ncr Co Replacement of capsule contents by diffusion
GB1575343A (en) * 1977-05-10 1980-09-17 Ici Ltd Method for preparing liposome compositions containing biologically active compounds
FR2416008A1 (en) * 1978-02-02 1979-08-31 Oreal LIPOSOME LYOPHILISATES
GB1575344A (en) * 1978-03-03 1980-09-17 Ici Ltd Method for the manufacture of liposome composition
JPS5770814A (en) * 1980-10-17 1982-05-01 Isamu Horikoshi Oral preparation of blood clotting eighth factor
JPS5782311A (en) * 1980-11-11 1982-05-22 Tanabe Seiyaku Co Ltd Production of liposome preparation
JPS5782310A (en) * 1980-11-11 1982-05-22 Tanabe Seiyaku Co Ltd Production of liposome preparation
IT8124920A0 (en) * 1981-11-09 1981-11-09 Magis Farmaceutici NEW PHARMACEUTICAL COMPOSITION.
EP0114577A1 (en) * 1983-01-21 1984-08-01 MAGIS FARMACEUTICI S.p.A. New pharmaceutical composition

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4217344A (en) * 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4235871A (en) * 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4298594A (en) * 1978-04-14 1981-11-03 Arthur D. Little, Inc. Xenobiotic delivery vehicles, method of forming them and method of using them
US4483847A (en) * 1980-06-28 1984-11-20 Warner-Lambert Company Process for the manufacture of a pharmaceutical composition with a retarded liberation of active material
US4389330A (en) * 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
US4485054A (en) * 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4540410A (en) * 1982-11-16 1985-09-10 Serono Pharmaceutical Partners Lyophilized compositions, preparation and use thereof
US4515736A (en) * 1983-05-12 1985-05-07 The Regents Of The University Of California Method for encapsulating materials into liposomes
US4532089A (en) * 1984-01-14 1985-07-30 Northwestern University Method of preparing giant size liposomes

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4971802A (en) * 1984-10-16 1990-11-20 Ciba-Geigy Corporation Liposomes of synthetic lipids
US4765987A (en) * 1985-08-30 1988-08-23 Adir & Cie Artificial surfactants, pharmaceutical compositions containing them and use thereof
US4877561A (en) * 1986-04-02 1989-10-31 Takeda Chemical Industries, Ltd. Method of producing liposome
US4963362A (en) * 1987-08-07 1990-10-16 Regents Of The University Of Minnesota Freeze-dried liposome mixture containing cyclosporin
US5830498A (en) * 1987-10-16 1998-11-03 Board Of Regents, The University Of Texas System Liposomal-polyene preliposomal powder and method for its preparation
US4999348A (en) * 1987-12-11 1991-03-12 Estee Lauder Inc. Liquid crystal containing cosmetic and pharmaceutical compositions and methods for utilizing such compositions
WO1989005636A1 (en) * 1987-12-22 1989-06-29 The Liposome Company, Inc. Spontaneous vesiculation of multilamellar liposomes
US4963297A (en) * 1987-12-22 1990-10-16 The Liposome Company, Inc. Spontaneous vesticulation of multilamellar liposomes
US5415867A (en) * 1988-04-20 1995-05-16 The Liposome Company, Inc. High ratio active agent: lipid complex
WO1989011272A1 (en) * 1988-05-20 1989-11-30 The Liposome Company, Inc. High ratio active agent:lipid complex
US5015483A (en) * 1989-02-09 1991-05-14 Nabisco Brands, Inc. Liposome composition for the stabilization of oxidizable substances
US5139803A (en) * 1989-02-09 1992-08-18 Nabisco, Inc. Method and liposome composition for the stabilization of oxidizable substances
US5246693A (en) * 1989-12-13 1993-09-21 L'oreal Cosmetic preparation for the care of the hair and use of the said composition
US5376380A (en) * 1990-08-21 1994-12-27 Daiichi Pharmaceutical Co., Ltd. Method of producing liposomal products from freeze or spray-dried preparations of liposomes
US5393530A (en) * 1990-12-11 1995-02-28 Bracco International B.V. Method for making liposomes of enhanced entrapping capacity toward foreign substances to be encapsulated
US5178875A (en) * 1991-01-14 1993-01-12 The Board Of Regents, The University Of Texas System Liposomal-polyene preliposomal powder and method for its preparation
US5965158A (en) * 1991-01-14 1999-10-12 The University Of Texas System & Board Of Regents Liposomal-polyene preliposomal powder and method for its preparation
WO1992012703A1 (en) * 1991-01-15 1992-08-06 University Of Miami Stimulation of hair growth by phospholipids
US5620703A (en) * 1991-10-11 1997-04-15 Max-Delbruck-Centrum Fur Molekulare Medizin Stimulating hematopoietic activity with carboplatin or lobaplatin
US5830499A (en) * 1994-09-27 1998-11-03 Rijksuniversiteit Leiden Phospholipid-and cholestrol-free aqueous composition for topical application to the skin
US7342099B2 (en) 1998-02-25 2008-03-11 The United States Of America As Represented By The Secretary, Department Of Health And Human Services cDNA encoding a gene BOG (B5T over-expressed gene) and its protein product
US6727079B1 (en) 1998-02-25 2004-04-27 The United States Of America As Represented By The Department Of Health And Human Services cDNA encoding a gene BOG (B5T Over-expressed Gene) and its protein product
US20040139485A1 (en) * 1998-02-25 2004-07-15 The Government Of The U.S. A, As Presented By The Secretary, Department Of Health And Human Services cDNA encoding a gene BOG (B5T over-expressed gene) and its protein product
US6992081B2 (en) 2000-03-23 2006-01-31 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US7119085B2 (en) 2000-03-23 2006-10-10 Elan Pharmaceuticals, Inc. Methods to treat alzheimer's disease
US7030239B2 (en) 2000-03-23 2006-04-18 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US20060276642A1 (en) * 2000-03-23 2006-12-07 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US6737420B2 (en) 2000-03-23 2004-05-18 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US20040214846A1 (en) * 2000-03-23 2004-10-28 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US20090074746A1 (en) * 2000-06-30 2009-03-19 Alzheimer's Collaboration Compounds to treat alzheimer's disease
US7432389B2 (en) 2000-06-30 2008-10-07 Elan Pharmaceuticals, Inc. Compounds for the treatment of Alzheimer's disease
US6846813B2 (en) 2000-06-30 2005-01-25 Pharmacia & Upjohn Company Compounds to treat alzheimer's disease
US7553831B2 (en) 2000-06-30 2009-06-30 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US7034182B2 (en) 2000-06-30 2006-04-25 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US7214715B2 (en) 2000-06-30 2007-05-08 Pharmacia & Upjohn Compounds to treat Alzheimer's disease
US20060211860A1 (en) * 2000-06-30 2006-09-21 Fang Lawrence Y Compounds for the treatment of Alzheimer's disease
US20020143177A1 (en) * 2000-06-30 2002-10-03 Beck James P. Compounds to treat alzheimer's disease
US20080227690A1 (en) * 2000-12-29 2008-09-18 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
US20020150566A1 (en) * 2001-03-23 2002-10-17 Kun-Liang Guan Method of inhibiting cancerous cell proliferation using Ras mutants of GDP-bound conformation
WO2003000202A3 (en) * 2001-06-22 2003-08-14 Advanced Inhalation Res Inc Particles for inhalation having rapid release properties
WO2003000202A2 (en) * 2001-06-22 2003-01-03 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
US20060178345A1 (en) * 2001-06-27 2006-08-10 Varghese John Substituted alcohols useful in treatment of Alzheimer's disease
US6982264B2 (en) 2001-06-27 2006-01-03 Elan Pharmaceuticals, Inc. Substituted alcohols useful in treatment of Alzheimer's disease
US20030083518A1 (en) * 2001-06-27 2003-05-01 Varghese John Substituted alcohols useful in treatment of Alzheimer's disease
US20060140847A1 (en) * 2003-02-18 2006-06-29 Bo Yang Method for introducing functional material into organic nanotube
WO2006057500A1 (en) 2004-11-24 2006-06-01 Seoul National University Industry Foundation Use of aimp2dx2 for the diagnosis and treatment of cancer
US9944713B2 (en) 2004-11-24 2018-04-17 Medicinal Bioconvergence Research Center Antibody specific to the AIMP2-DX2
US20080171795A1 (en) * 2005-03-21 2008-07-17 Life-Care Innovations Pvt. Ltd. Novel Inter and Intra Multilamellar Vesicular Composition
US20100260830A1 (en) * 2009-04-08 2010-10-14 Brian A Salvatore Liposomal Formulations of Tocopheryl Amides
US10195166B2 (en) 2013-10-29 2019-02-05 The Catholic University Of Korea Industry-Academic Cooperation Foundation Methods for treating hepatitis C virus infectious disease
WO2016100716A1 (en) 2014-12-18 2016-06-23 Vasant Jadhav Reversirtm compounds

Also Published As

Publication number Publication date
GB8520405D0 (en) 1985-09-18
GB8527287D0 (en) 1985-12-11
EP0171710A2 (en) 1986-02-19
JPH0545568B2 (en) 1993-07-09
EP0171710A3 (en) 1987-05-27
GB2168670A (en) 1986-06-25
JPS6150912A (en) 1986-03-13

Similar Documents

Publication Publication Date Title
US4673567A (en) Process for preparing liposome composition
US4762720A (en) Process for preparing liposome compositions
US5567433A (en) Liposome preparation and material encapsulation method
US4235871A (en) Method of encapsulating biologically active materials in lipid vesicles
US4857319A (en) Method for preserving liposomes
US4241046A (en) Method of encapsulating biologically active materials in lipid vesicles
US4485054A (en) Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
EP0498471B1 (en) Liposomes comprising a guanidino aminoglycoside
EP0292403B1 (en) Prostaglandin-lipid formulations
US4515736A (en) Method for encapsulating materials into liposomes
US4370349A (en) Process for preparing freeze-dried liposome compositions
JPH0761947B2 (en) Anthracycline antitumor drug encapsulated in phospholipid micelle particles
WO1985000751A1 (en) Lipid vesicles prepared in a monophase
US5429823A (en) Phospholipid composition and liposomes made therefrom
EP0416527A2 (en) Prostaglandin-containing liposome preparations
JPH06345663A (en) Liposome preparation containing vancomycin
WO1989005636A1 (en) Spontaneous vesiculation of multilamellar liposomes
JPH0362696B2 (en)
GB1575344A (en) Method for the manufacture of liposome composition
JPH10236946A (en) Improved production of double liposome pharmaceutical preparation
JPH02295933A (en) Production of liposome containing plasminogen activating factor sealed therein with high sealing purity
JP3118869B2 (en) Fat body composition containing prostaglandins
IE46572B1 (en) Method for the manufacture of liposome compositions

Legal Events

Date Code Title Description
AS Assignment

Owner name: SHIONOGI & CO., LTD., FUKUSHIMA-KU, OSAKA, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:JIZOMOTO, HIROAKI;REEL/FRAME:004442/0478

Effective date: 19850719

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12

REMI Maintenance fee reminder mailed